Management and Antithrombotic Treatment of APS in Pregnancy With proper management, more than 70% of pregnant women with

antiphospholipid syndrome will deliver a viable live infant (110). Ideally, preconception counseling gives the physician the opportunity to understand the specific con- text of each patient with the syndrome and to outline the risks of pregnancy and treatment. Pregnancy should be discouraged in all women with important pulmonary hypertension because of the high risk of maternal death (111), and should be postponed in the setting of uncontrolled hypertension or recent thrombotic events, especially stroke (111). A complete profile of antiphospholipid anti- bodies, including repeated anticardiolipin and lupus anti- coagulant, should be available before planning of pregnancy. However, these tests do not need to be repeated during pregnancy, since subsequent negative results (after diagnostic, repeatedly positive tests) do not eliminate the risk of complications (111). Patients should be counseled in all cases regarding symptoms of thrombosis and thromboembolism and should be educated regarding, and examined frequently for, the signs or symptoms of thrombosis or thromboembolism, severe preeclampsia, or decreased fetal movement. We recommend frequent prenatal visits, at least every 2-4 weeks before midgestation and every 1-2 weeks thereafter. Human chorionic gonadotropin (hCG) values in the first trimester can be followed to evaluate the viability of the pregnancy. If hCG levels are increasing normally (ie, doubling every 2 d) in the first month of pregnancy, a successful out-come is predicted in 80-90% of cases. However, when the increases are abnormal (ie, slower), a poor outcome is predicted in 70-80% of cases. In patients with poor obstetric histories, evidence of preeclampsia, or evidence of fetal growth restriction, ultrasonography is recommended every 3-4 weeks starting at 18-20 weeks gestation. The objectives of prenatal care in the second and third trimesters are close observation for maternal hypertension, proteinuria and other features of preeclampsia, frequent patient assessment, obstetric ultrasound to assess fetal growth and amniotic fluid volume, and appropriate fetal surveillance testing. Surveillance testing should begin at 32 weeks gestation, or earlier if the clinical situation for placental in- sufficiency is suspected, and should continue at least every week until delivery. Regular and coordinated medical consultation every 2-4 weeks, especially in women with systemic lupus erythematosus, is recommended. In patients with uncomplicated APS, ultrasonography is recommended at 30-32 weeks gestation to assess fetal growth. Lagging fetal growth may reflect uteroplacental insufficiency in patients with APS (10). Uterine and umbilical artery Doppler assessments are widely used in Europe to assess the risk for preeclampsia, placental insufficiency, and fetal growth restriction after the 20th week of gestation, and normal examinations have high negative predictive values (112). The goals of treatment in pregnant women with antiphospholipid syndrome are to improve maternal and fetal- neonatal outcomes by keeping to a minimum the risks of the recognised

complications of the disorder, including maternal thrombosis, fetal loss, preeclampsia, placental insufficiency, and fetal growth restriction, and the need for iatrogenic preterm birth (75). The optimal treatment of pregnant women with antiphospholipid antibodies and 1 or more fetal losses after 10 weeks gestation without thrombosis is controversial (113). Earliest treatment for recurrent pregnancy loss associated with aPL was a combination of high dose prednisone and low-dose aspirin, with successful outcome in 75% of treated pregnancies. High maternal and fetal morbidity resulted, however, including gestational diabetes, hypertension, and premature rupture of membranes. A randomized controlled study of prednisone and aspirin as compared with heparin and aspirin showed low-dose subcutaneous heparin with low-dose aspirin to be equally efficacious with less morbidity (114). Moreover, a Cochrane analysis concluded that intravenous immunoglobulins were associated with an increased risk of pregnancy loss or premature birth, compared with heparin and low-dose aspirin (115). Then the studies focused on the effectiveness of therapy with UFH, LMWH and low-dose aspirin and their possible association, lead to conflicting results. In two trials (116, 117), the proportion of successful pregnancies substantially improved with the addition of unfractionated heparin to low-dose aspirin. Two other randomised trials (118,119), both using low-molecular-weight heparin, proved negative. Additionally, two studies recorded no differences in pregnancy outcomes when comparing unfractionated heparin with low-molecular-weight heparin, both combined with aspirin (120, 121). Moreover, low doses of subcutaneous unfractionated heparin (5000 units twice daily) appear to be as effective as high-dose heparin (10000 units twice daily) (117, 122). Finally, several observational studies have reported pregnancy success rates of 79100% with low-dose aspirin alone (123-129). Other available studies indicated that aspirin (5081 mg/d) compared with placebo or usual care did not reduce the rate of pregnancy loss (130, 131). Despite the obvious controversies raised by these trials, a 2005 Cochrane systematic review concluded that women with recurrent miscarriage and antiphospholipid syndrome should be given a combination of heparin 5000 IU subcutaneously twice daily and low-dose aspirin (115). Expert guidelines recommend the combination of aspirin with either low-dose heparin or low- molecularweight heparin (132). Heparin is the anticoagulant drug of choice during pregnancy (133). Heparin does not cross the placenta and is widely considered safe for the embryo-fetus. Of the 2 clinically available forms, the low molecular weight heparin (LMWH) preparations offer some advantages over unfractionated heparin (UFH). Both UFH and LMWH act primarily by binding to antithrombin to catalyze the molecule binding to and altering the activity of serine protease procoagulants. UFH enhances the activity of antithrombin for Factor Xa and thrombin, whereas the predominant effect of LMWH is via antithrombin- mediated anti-Factor Xa activity. UFH has complex pharmacokinetics that ultimately leads to a somewhat unpredictable anticoagulant response. Also, the bioavailability of the UFH after subcutaneous (SC) injection is reduced compared with intravenous infusion.

LMWH, in contrast, is less likely to bind nonspecifically to various circulating protein or cell surfaces and so has improved pharmacokinetics and bioavailability when given SC. In addition, LMWH is less likely than UFH to cause heparin-induced thrombocytopenia (HIT) and osteoporosis, though the latter is infrequent (1-2% of cases) in women treated during pregnancy (100, 103). Importantly, counsel the patient regarding potential adverse effects of heparin. Bone density studies should be considered in patients receiving anticoagulation with heparin or LMWH may be important in women who have been treated in a previous pregnancy or are planning pregnancy. For the most part, the longer half-life of LMWH is seen as an advantage because it allows once- or twice-daily dosing regimens to be used. Pregnant patients with antiphospholipid syndrome can be classified in: Patients affect by antiphospholipid syndrome without a previous thrombotic event (diagnosed because of ob- stetric event(s):

(a) patients with recurrent early (preembryonic or embr- yonic) miscarriage and no other features of anti- phospholipid syndrome, or (b) those with one or more previous fetal deaths (at more than 10 weeks gestation) or previous early delivery (at less than 34 weeks gestation) because of severe pre-eclampsia or placental insufficiency.

Patients with acute VTE within several months of conception or during pregnancy or Recurrent VTE (2 or more prior VTEs). Table Table55 summarises recommended treatments for these groups.

o the Evidence-Based Clinical Practice Guidelines of American College of Chest Physicians (132) suggest that women with antiphospholipid antibodies and a history of 2 or more early pregnancy losses or 1 or more late pregnancy losses who have no prior history of thrombosis receive treatment with combination aspirin and heparin (unfractionated or lowmolecular-weight) during pregnancy. Aspirin (81 mg/d) should be started with attempted conception; most investigators recommend, in fact, preconceptional aspirin because of its possible beneficial effect on early stages of implantation (123). Heparin (5000-10 000 units every 12 hours) or lowmolecular-weight heparin in prophylactic doses (Enoxaparin 40 mg SC every 24 h) should be started when a viable intrauterine pregnancy is documented and continued until late in the third trimester (134). Patients with a history of thrombosis should be fully anticoagulated with an adjusted-dose UFH or LMWH regimen (UFH SC every 12 h or Enoxaparin 1 mg/kg SC every 12 h) for at least 6 months from the initial presentation with VTE. Women who are on warfarin should discontinue the warfarin before 6 weeks of gestation. Some clinicians favor discontinuing the warfarin when the patient initiates attempting to conceive, replacing it with UFH or LMWH. If the patient reaches 6 months of anticoagulation during the pregnancy, consideration of reducing the degree of anticoagulation (eg, to prophylactic UFH or LMWH) is reasonable, especially in preparation for epidural anesthesia. Following delivery, the UFH or LMWH should be restarted and bridged to warfarin. About Peripartum Heparin Management, as Cesarean delivery has been cited as a risk for VTE (96,107). Recommendations for thromboprophylaxis (132, 133) suggest that those women receive thromboprophylaxis with prophylactic LMWH or UFH, or by mechanical prophylaxis with lower extremity compression devices while hospitalized. Low- to moderate-risk patients on LMWH can be transitioned to UFH (because of its shorter half-life) at 36 to 37 weeks gestation in an effort to improve the likelihood of epidural anesthesia if preterm labor occurs. Patients should be advised that if they suspect spontaneous labor, heparin should be discontinued. For induction or scheduled cesarean, adjusted-dose heparin and intermediate-dose LMWH should be discontinued 24 hours before the scheduled admission. Prophylactic heparin should be discontinued at least 12 hours prior. For high-risk patients, reasonable options include reducing the heparin dose to 5000 units SC twice a day or using a judiciously applied continuous infusion of heparin during labor, with discontinuation when delivery is estimated to be 1 to 2 hours away. In most cases, heparin should be restarted 6 to 8 hours following delivery or cesarean section. Regarding high-risk patients, continuous infusion should be restarted after delivery when the risk of bleeding has decreased (usually 2 to 4 hours after delivery). The American Society of Regional Anesthesia (ASRA) has made recommendations regarding anticoagulation and regional anesthesia. Regional anesthesia is contraindicated in patients less than 24 hours from their last dose of twice-daily LMWH. For prophylactic LMWH, regional anesthesia can be placed 10 to 12 hours duration from the last dose of LMWH heparin. The neuraxial catheter should be removed 2 hours before the first LMWH dose. Intravenous heparin can be initiated 1 hour following neuraxial anesthesia, with catheter removal 2 to 4 hours after the last heparin dose. SC heparin dosed twice daily with a

total dose less than 10,000 units of UFH per day is not a contraindication to neuraxial anesthesia. However, neuraxial anesthesia at doses greater than 10,000 units of UFH or dosing at a frequency greater than twice daily dosing has not been established to be safe (135). Therapy (including aspirin and heparin) can reduce the rate of fetal loss to 25%, as described by Cowchock et al. (114). In order to reduce the risk of postpartum deep vein thrombosis, antithrombotic coverage of the post-partum period is recommended in all women with antiphospholipid syndrome, with or without previous thrombosis (132). Generally, women with previous thrombosis will need longterm anticoagulation, and most experts prefer switching the treatment to warfarin, as soon as the patient is clinically stable after delivery, to limit further risk of heparin- induced osteoporosis and bone fracture. In patients with no previous thrombosis, the recommendation is prophylactic dose heparin or low-molecular-weight heparin therapy for 4-6 weeks after delivery (132), although warfarin is an option. Both heparin and warfarin are safe for breast- feeding mothers (136). A retrospective study of subsequent thrombosis in 65 patients with prior pregnancy events not routinely treated with prophylaxis after the immediate post- partum period, has shown such patients to have a 59% rate of thrombosis over 10 years of follow up; patients who continued on low-dose aspirin, however, had a rate of 10% (58). Based on these data, the current recommendation may be low-dose aspirin postpartum indefinitely. About the other pregnancy complications, data from meta-analysis (137) have shown their significant reduction in women at high risk for pre-eclampsia who were given antiplatelet agents (mostly aspirin). In all clinical trials, maternal and fetal-neonatal outcomes in pregnancies progressing beyond 20 weeksgestation were benign, with the frequencies of fetal death, preeclampsia, severe placental insufficiency, and iatrogenic preterm birth close to those of the general obstetric population. Results from randomised trials do not define optimum treatment for women with fetal death (>10 weeks gestation) or previous early delivery (<34 weeks gestation) due to severe preeclampsia or placental insufficiency. Most experts recommend low-dose aspirin and either prophylactic or intermediate-dose heparin (75, 115, 132). Vitamin K antagonists are teratogenic and should be avoided between 6 and 12 weeks of gestation. Because of the risk of fetal bleeding thereafter (132, 136) warfarin after 12 weeks gestation should be given only in exceptional circumstances. Probably there is a relationship of aPL to infertility but it has been controversial until now. Although prevalence of aPL antibodies is increased in patients undergoing in vitro fertilization (IVF), a recent prospective study found that aspirin and heparin treatment of IVF patients with positive aPL antibodies and history of failed IVF cycles does not improve IVF cycle outcome (138). Several potential new therapeutic approaches for APS are emerging (Table (Table66).

Table 6

- Potential future therapies for antiphospholipid syndrome. But most of these possible future therapies (clopidogrel, rivaroxaban, statins, rituximab, and other new anticoagulantdrugs) are for non-pregnant patients. The only new drugs for APS that pregnant women can use are dipyridamole and hydroxychloroquine. Combination treatment with aspirin plus dipyridamole have shown higher efficacy than has aspirin alone in patients with stroke. Such combination might be considered in selected patients with antiphospholipid syndrome in whom warfarin is not effective or safe. Observational studies have suggested an antithrombotic effect of hydroxychloroquine in patients with antiphospholipid antibodies, most of whom have systemic lupus erythematosus (49, 139, 140). Furthermore, results from basic studies have shown a dose- dependent reduction by hydroxychloroquine of platelet activation and clotting induced by antiphospholipid antibodies (141, 142). Hydroxychloroquine directly inhibits the binding of antiphospholipid antibody- 2glycoprotein-1 complexes to phospholipid surfaces (143). An additional and previously unrecognised role of hydroxychloroquine in prevention of pregnancy loss is suggested by the description of its pro- tective effect of the annexin A5 shield formed over phospholipid bilayers from damage induced by antiphospholipid antibodies (144). In view of the excellent safety profile, including the absence of any adverse effects on the fetus-neonate (145), and the absence of associated bleeding, hydroxychloroquine should be considered for an adjuvant antithrombotic role in patients with systemic lupus erythematosus who are positive for antiphospholipid antibodies. Patients with primary antiphospholipid syndrome and recurrent thrombosis despite adequate anticoagulation, who have difficulty maintaining adequate anti- coagulation intensity, or have a high-risk profile for major haemorrhage, might also benefit from hydroxychloroquine treatment. Furthermore, recent data from an experimental model of aPL antibody-induced pregnancy losses in mice (33) suggest that the therapeutic effect of heparin in the disorder might be due to the inhibition of complement rather than its inhibition of coagulation. These data, if generalizable to human APS-related pregnancy losses, have raised the intriguing possibility of novel non anticoagulant approaches to treatment.

Approach Considerations Pregnant women with APS are considered high-risk obstetric patients, and medical care is instituted with this in mind. In patients receiving or recently treated with corticosteroid therapy, administer supplementation to cover the labor or cesarean delivery. Pregnancy in itself is not harmful to the mother or the baby unless added work related to the newborn, as well as emotional stress in the family, proves to be too much for a particular patient. Therapeutic abortions are generally not indicated in pregnant women with autoimmune disease. Epidural anesthetic is not recommended if the mother has a marked drop in the maternal platelet count. The use of forceps or the vacuum extractor should be individualized. No evidence indicates adverse effects related to breastfeeding, although breastfeeding is not recommended if high doses of cytotoxic or immunosuppressive agents are required. Obstetric Care Patients should be counseled in all cases regarding symptoms of thrombosis and thromboembolism and should be educated regarding, and examined frequently for, the signs or symptoms of thrombosis or thromboembolism, severe preeclampsia, or decreased fetal movement. Ultrasonography is recommended every 3-4 weeks starting at 18-20 weeks gestation, in patients with a poor obstetric history, evidence of preeclampsia, or evidence of fetal growth restriction. Human chorionic gonadotropin (hCG) values in the first trimester can be followed to evaluate the viability of the pregnancy. If hCG levels are increasing normally (ie, doubling every 2 days) in the first month of pregnancy, a successful outcome is predicted in 80-90% of cases. However, when the increases are abnormal (ie, slower), a poor outcome is predicted in 70-80% of cases. In patients with uncomplicated APS, ultrasonography is recommended at 30-32 weeks gestation to assess fetal growth. Lagging fetal growth may reflect uteroplacental insufficiency in patients with APS. Drugs such as chloroquine and cytotoxic agents are not recommended during pregnancy; patients should stop taking these drugs several months prior to becoming pregnant. Splenectomy during the early second trimester or at the time of cesarean delivery may be considered in patients with thrombocytopenia refractory to glucocorticoid therapy. Anticoagulation therapy Anticoagulation with heparin is recommended in APS and pregnancy with a history of a thromboembolic event. Low-molecular-weight heparin (LMWH) may be used in these patients. Importantly, counsel the patient regarding potential adverse effects of heparin. Heparin-induced osteoporosis occurs in 1-2% of cases. Initiation of heparin in the face of a failing pregnancy should be undertaken with caution due to bleeding risks.

Bone density studies should be considered in patients receiving anticoagulation therapy with heparin or LMWH due to the risks of osteopenia. This may be most important in women who have been treated in a previous pregnancy or are planning pregnancy. Warfarin may be substituted for heparin during the postpartum period to limit further risk of heparin-induced osteoporosis and bone fracture. In women without a history of a thromboembolic event, optimal therapy is not as clear. Anticoagulation may decrease recurrent pregnancy loss in this group of women. Low-dose aspirin combined with prophylactic doses of heparin or LMWH appears to be superior to aspirin therapy alone or maternal steroids. Intravenous immunoglobulin Infused immunoglobulins may modulate aCL antibodies levels by the following 3 mechanisms:

Antiidiotypic antibodies may be present in the intravenous immunoglobulin (IVIG) preparation; these antiidiotypic antibodies may bind autoantibodies to form idiotypeantiidiotype dimers, resulting in neutralization of autoantibody effects. Antiidiotype antibodies may bind and downregulate B-cell receptors, resulting in a decrease in autoantibody production Antiidiotype antibodies might bind receptors of regulatory T cells, resulting in suppression of lymphokine production and decreased activation of autoantibody-producing B cells Nonobstetric Care Immunosuppressive agents are recommended for patients with SLE with secondary APS. Thromboprophylaxis is also recommended. In addition, patients should be evaluated for renal disease, (glomerulonephritis, end-stage renal disease), anemia, and thrombocytopenia. (See the Table below.) Table. Proposed Management for Women With aPL Antibodies (Open Table in a new window) Management Feature Pregnant APS with prior fetal death or recurrent pregnancy loss Heparin in prophylactic doses (15,00020,000 U of unfractionated heparin or equivalent per day) administered subcutaneously in divided doses with lowdose aspirin daily Nonpregnant Optimal management uncertain; options include no treatment or daily treatment with low-dose aspirin

Calcium and vitamin D supplementation

APS with prior thrombosis or stroke

Heparin to achieve full anticoagulation (does not cross the placenta)

Warfarin administered daily in doses to maintain international normalized ratio of =3 No treatment or daily treatment with low-dose aspirin; optimal management uncertain

APS without prior pregnancy loss or thrombosis

No treatment or daily treatment with lowdose aspirin or daily treatment with prophylactic doses of heparin plus lowdose aspirin; optimal management uncertain High-dose IVIG at 400-1500 mg/kg/day for several days

LGBSS

IVIG at 400-1500 mg/kg/d for several days

aPL Antibodies Without APS No treatment LAC or medium to high level of aCL IgG No treatment Low levels of aCL IgG, only aCL IgM, or only aCL IgA without LA, aPL, or aCL No treatment

No treatment

Note the following:

The medications shown should not be used in the presence of contraindications Close obstetric monitoring of the mother and fetus is necessary in all cases The patient should be counseled in all cases regarding symptoms of thrombosis and thromboembolism Cardiac Valvular Surgery and Splenectomy Patients with APS, especially secondary APS, may require surgical interventions for longstanding complications of their autoimmune disorder. Cardiac valvular surgery is recommended in patients with severe aortic regurgitation due to the noninfectious vegetations that are seen as a result of APS.

Splenectomy is recommended in patients with the chronic form of idiopathic thrombocytopenic purpura and is associated with remission in approximately 75% cases. Thromboprophylaxis is recommended for any abdominal or orthopedic surgery. Manage thrombotic or hemorrhagic complications. Be aware of associated thrombocytopenia, and use laboratory methods of perioperative anticoagulation monitoring in the setting of prolonged clotting times. Consultations and Follow-up The patient should be informed about potential maternal and obstetric problems, including fetal loss, thrombosis or stroke, PIH, fetal growth restriction, and preterm delivery. Consultation with specialists in Maternal-Fetal Medicine and Rheumatology should be considered. In women with APS and 1 or more prior thrombotic events, lifelong anticoagulation with warfarin may be advisable to avoid recurrent thrombosis. An assessment by a rheumatologist or hematologist may also be helpful. Medication Summary In women with well-recognized obstetric APS, anticoagulant prophylaxis is recommended during pregnancy and the postpartum period. Pregnant women with APS are considered at risk for thrombosis and pregnancy loss. Data suggest low-dose aspirin and heparin (either unfractionated heparin or LMWH) to be the treatments of choice for prevention of pregnancy loss in pregnant women with APS and previous pregnancy losses. Pregnant women with APS and a history of thrombosis but no pregnancy loss require only treatment with heparin. Treatment is optional for patients with no history of pregnancy loss or thrombosis. Anticoagulants, Hematologic Class Summary Unfractionated intravenous (IV) heparin and fractionated subcutaneous (SC) LMWH are the 2 choices for initial anticoagulation therapy. Warfarin therapy may be initiated in the postpartum stage. These are used in the treatment or prophylaxis of clinically evident intravascular thrombosis. Special precaution should be exercised in obstetrical emergencies or massive liver failure. Similar to unfractionated heparin, LMWHs are a class of anticoagulants termed glycosaminoglycans. LMWHs are derived from unfractionated heparin but have smaller, more standard average masses than does heterogeneous unfractionated heparin. Unlike standard heparin, LMWHs have higher specificity for factor Xa and have fewer effects on platelet activity. As a result, LMWH may cause bleeding less often, while still retaining anticoagulant effects. LMWHs may be associated with less risk of heparin-induced osteoporosis. Heparin

Heparin is indicated to decrease the risk of thrombosis and pregnancy loss in pregnant women with APS.

It augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. Heparin does not actively lyse but is able to inhibit further thrombogenesis. The drug prevents reaccumulation of clot after spontaneous fibrinolysis. heparin lock solution 10units/mL 100units/mL injectable solution 1000units/mL 2500units/mL 5000units/mL 10,000units/mL 20,000units/mL premixed IV solution 20,000units/500mL 25,000units/250mL 25,000units/500mL DVT & PE Prophylaxis 5000 units SC q8-12hr, OR 7500 units SC q12hr Treatment 80 units/kg IV bolus, THEN continuous infusion of 18 units/kg/hr, OR 5000 units IV bolus, THEN continuous infusion of 1300 units/hr, OR 250 units/kg (alternatively, 17,500 units) SC, THEN 250 units/kg q12hr Dosing considerations Numerous concentrations available; extreme caution is required to avoid medication error Acute Coronary Syndromes PCI Without GPIIb/IIIa inhibitor: Initial IV bolus of 70-100 units/kg (target ACT 250-300 sec) With GPIIb/IIIa inhibitor: Initial IV bolus of 50-70 units/kg (target ACT >200 sec) STEMI Patient on fibrinolytics: IV bolus of 60 units/kg (max: 4000 units), THEN 12 units/kg/hr (max 1000 units/hr) as continuous IV infusion Dose should be adjusted to maintain aPTT of 50-70 sec Unstable Angina/NSTEMI Initial IV bolus of 60-70 units/kg (max: 5000 units), THEN initial IV infusion of 12-15 units/kg/hr (max: 1000 units/hr) Dose should be adjusted to maintain aPTT of 50-70 sec Dosing considerations

Numerous concentrations available; extreme caution is required to avoid medication error

Anticoagulation Intermittent IV injection 8000-10,000 units IV initially, THEN 50-70 units/kg (5000-10,000 units) q4-6hr Continuous IV infusion 5000 units IV injection, followed by continuous IV infusion of 20,000-40,000 units/24 hr Dosing considerations Numerous concentrations available; extreme caution is required to avoid medication error Catheter Patency Prevention of clot formation within venous and arterial catheters Use 100 units/mL; instill enough volume to fill lumen of catheter Dosing considerations Numerous concentrations available; extreme caution is required to avoid medication error Amount and frequency depends on catheter volume and type Peripheral heparin locks typically are flushed q6-8hr Dosing Modifications Hepatic impairment: Caution is advised; dosage adjustment may be required Mechanism of Action Mechanism for low dose: Inactivates factor Xa and inhibits conversion of prothrombin to thrombin Mechanism for high dose: Inactivates factors IX, X, XI, and XII and thrombin and inhibits conversion of fibrinogen to fibrin Also inhibits activation of factor VIII Absorption Bioavailability: 22-40% Onset: IV (immediate); SC (20-30 min) Peak plasma time: 2-4 hr Distribution Protein bound: Extensive Metabolism Metabolized in the liver (partial) and reticuloendothelial system (partial) Metabolites: None

Elimination Half-life: 60-90 min average (longer at higher doses) Dialyzable: No Excretion: Urine

Enoxaparin (Lovenox)

Enoxaparin, an LMWH, is indicated to decrease the risk of thrombosis and pregnancy loss in pregnant women with APS. It prevents deep venous thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases the inhibition of factor Xa. Increased risk of bleeding with doses of 1.5 mg/kg/day or 1 mg/kg q12hr multidose vial 100mg/mL (3mL vial) prefilled syringe 30mg/0.3mL 40mg/0.4mL 60mg/0.6mL 80mg/0.8mL 100mg/mL 120mg/0.8mL 150mg/mL Dosing considerations Risk of serious adverse reactions increases in the elderly Body weight <45 kg may require dose adjustment LMWH; antithrombotic that inhibits factor Xa by increasing inhibition rate of clotting proteases that are activated by antithrombin III Generally does not increase PT or PTT Absorption Bioavailability: 92% Onset: 3-5 hr Duration: 12 hr (40 mg)

Peak plasma time: 3-5 hr (ie, maximum anti-factor Xa and antithrombin activity) AUC: 14.26 hrIU/mL Distribution Vd: 4.3 L Metabolism Metabolized by liver via desulfation and/or depolymerization to lower molecular weight species Elimination Half-life: 4.5 hr (single dose); 7 hr (repeated dosing) Total body clearance: 26 mL/min

Dalteparin (Fragmin)

Dalteparin is indicated for the prevention of DVT, which may lead to PE. It enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, dalteparin preferentially increases the inhibition of factor Xa. The average duration of treatment is 7-14 days. injectable solution 10,000 International Units/mL 25,000 International Units/mL prefilled syringe 2500 International Units/0.2mL 5000 International Units/0.2mL 7500 International Units/0.3mL Extended VTE Treatment in Patients with Cancer 200 units IU/kg SC qDay for 30 days, THEN Months 2-6: 150 units/kg SC qDay Not to exceed 18,000 units daily Treatment Duration: 5-10 days usual Severe Mobility Restriction: 5000 units SC qDay Thrombocytopenia: Dose Reduction Plts 50,000-100,000/mm: Reduce daily dose by 2500 units until 100,000/mm Plts <50,000/mm, discontinue until >50,000/mm Renal Impairment, Severe: Dose Reduction CrCl < 30 mL/min: Monitor anti-Xa level to determine appropriate dose

Deep Vein Thrombosis Prophylaxis Hip Replacement PostOp Start 2500 units SC 4-8 hr postsurgery, THEREAFTER 5000 units qDay PreOp Start On day of surgery: 2500 IU SC within 2 hours presurgery, THEN 2500 units SC 4-8 hr postsurgery, THEREAFTER 5000 units SC qDay (administration: At least 6 hr between first post-op dose & Post-op Day 1 dose) Evening before Surgery: 5000 units SC 10-14 hr presurgery, THEN 5000 units SC 4-8 hr postsurgery, THEREAFTER 5000 units SC qDay Abdominal Surgery 2500 IU SC 1-2 hr preop, THEREAFTER 2500 units SC qDay High risk of thromboembolic complications (eg, malignancy): 5000 units SC evening before surgery, THEN 5000 units qDay (first dose may be evenly split in a preop & postop dose) Unstable Angina & Non-Q-Wave MI 120 IU/kg SC q12hr for 5-8 days (concurrent with aspirin 75-165 mg qDay) Not to exceed 10,000 units/dose or 18,000 units/day Treatment Duration: Continue until patient stabilized; 5-10 days usual Anticoagulation Therapy (Off-label) 200 IU/kg SC qDay or 100 units/kg SC q12hr Other Indications & Uses Symptomatic venous thromboembolism (DVT/PE) treatment to reduce recurrence in patients with cancer Off-label: Treatment of thromboembolism during pregnancy, DVT prophylaxis during knee replacement surgery, neurosurgery, trauma, burns, pediatric Mechanism of Action LMW heparin with antithrombotic properties; enhances inhibition of Factor Xa & thrombin by antithrombin, minimal effect on APTT Pharmacokinetics Half-Life: 3-5 hr Onset of action: 1-2 hr (anti Xa activity) Peak plasma time: 4 hr Duration: >12hr Peak plasma concentration: 0.19 IU/mL (2500 IU dose) Protein binding: Low

Bioavailability: 81-93% Vd: 40-60 mL/kg Excretion: Urine Clearance: 15-25 mL/hr/kg (dose-dependent)

Antiplatelet Agents, Hematologic Class Summary Randomized, controlled trials demonstrate improved fetal survival when pregnant women with APS and prior pregnancy losses are treated with low-dose aspirin plus heparin, compared with low-dose aspirin alone. Aspirin (Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin, Ibu, Advil, Motrin)

Aspirin's antiplatelet effect is indicated to decrease the risk of thrombosis and pregnancy loss in pregnant women with APS. It inhibits prostaglandin synthesis, preventing the formation of platelet-aggregating thromboxane A2. Aspirin is used in low dose to inhibit platelet aggregation and to improve complications of venous stasis and thrombosis. tablet 81mg 325mg 500mg tablet, delayed release 162mg 325mg 500mg tablet, chewable 75mg 81mg tablet, enteric coated 81mg 162mg 325mg 650mg gum, chewing, oral 227mg Pain & Fever 325-650 mg PO/PR q4-6hr PRN

Controlled/extended/delayed-release products (enteric-coated): 650-1300 mg PO q8hr; not to exceed 3.9 g/day Acute Coronary Syndrome For use as adjunctive antithrombotic effects for ACS (ST-segment elevation myocardial infarction [STEMI], unstable angina [UA]/non-ST-segment elevation myocardial infarction [NSTEMI])

Acute symptoms 160-325 mg PO; chew nonenteric-coated tablet upon presentation (within minutes of symptoms) If unable to take PO, may give 300-600 mg suppository PR Maintenance (secondary prevention) 75-81 mg PO qDay indefinitely (preferred dose); may give 81-325 mg/day Regimen may depend on coadministered drugs or comorbid conditions Coadministered with ticagrelor: 81 mg PO qDay Percutaneous transluminal coronary angioplasty Adjunctive aspirin therapy to support reperfusion with primary PCI (with or without fibrinolytic therapy) Preoperative dose: 162-325 mg PO before procedure Maintenance: 81 mg PO qDay indefinitely (preferred dose) may give 81-325 mg/day Regimen may depend on coadministered drugs or comorbid conditions Coadministered with ticagrelor: 81 mg PO qDay Ischemic Stroke & Transient Ischemic Attack 50-325 mg/day PO within 48 hours of stroke or TIA, then 75-100 mg/day PO Osteoarthritis Up to 3 g/day PO in divided doses Rheumatoid Arthritis 3 g/day PO in divided doses; increased PRN for anti-inflammatory efficacy (target plasma salicylate, 150-300 mcg/mL) Spondyloarthropathy 3.6-5.4 g/day PO in divided doses; monitor serum concentrations Colorectal Cancer (Off-label) Prophylaxis 600 mg/day PO Decreases risk of developing hereditary colorectal cancer (ie, Lynch syndrome) by 60% if taken daily for at least 2 years Dosing Modifications Renal impairment

CrCl >10 mL/min: Dose adjustment not necessary CrCl <10 mL/min: Not recommended Hepatic impairment Severe liver disease: Not recommended